A multitude of events contribute to the ultimate outcome following SCI, including neuron, oligodendrocyte and axonal loss, demyelination, glial scar formation and inhibitory molecule deposition, and endogenous capacity for regeneration. These events define critical points for investigation of the mechanism of action of interventions that affect functional recovery. The development of cell-based therapeutic strategies, including cultured Schwann and olfactory ensheathing cells, fetal spinal cord tissues, and embryonic stem cell (ES)-derived progenitors, is of strong current interest for SCI. In particular, CNS Stem Cells (CNS-SC), which have the ability to migrate and differentiate into neurons, oligodendrocytes and astrocytes upon transplantation could benefit the injured spinal cord in a variety of ways. These include differentiation and functional engraftment of new neurons and oligodendrocytes, modifying the regenerative or remyelination potential of host cells, and decreasing host glial scaring or deposition of inhibitory matrix molecules (e.g. proteoglycans). We have found that cells from CNS-SC banks initiated from prospectively isolated human fetal brain using monoclonal antibody based fluorescence activated cell sorting (FACS) survive and engraft in contusion-injured immunodeficient NOD-scid mice. Contusion-injured mice transplanted with human CNSSC neurospheres 9 days post-SCI show improved recovery of open field locomotor function. These highly enriched human CNS-SC can be reproducibly isolated, are capable of long term growth in culture as neurospheres, and our preliminary data suggest that they maintain their capacity to differentiate into neurons and oligodendrocytes in the injured spinal cord. The objective of this proposal is to experimentally test the basis for the observed functional recovery, testing the hypothesis that human CNS-SC either differentiate and functionally engraft or modify the host response to injury as described above. Further, we will also test the hypothesis that exercise will act synergistically with cell transplantation to improve locomotor recovery, based on its known role in promoting neurogenesis and our data demonstrating enhancement of locomotor outcome in contusion-injured mice in a voluntary wheel running paradigm.